DESCRIPTION: (Applicant's Abstract) The purpose of this investigation is to evaluate the effect of HIV infection, drug use and other factors on the progression of hepatitis C. The observation of heterogenous outcomes after hepatitis C virus (HCV) infection suggests the hypothesis that viral, genetic, and environmental factors affect disease progression. To examine the relative importance of multiple factors, in a representative setting and with appropriate power, a series of integrated experiments have been designed for specimens from a large cohort (ALIVE) of injecting drug users (IDUs) who have been followed semiannually since 1988. The study population is 1,265 HCV-infected IDUs, including 378 coinfected with HIV at enrollment. By prospectively assessing liver enzymes and actively ascertaining clinical evidence of hepatic failure or death on all participants and evaluating liver biopsies randomly obtained from 210 individuals, an estimated 50 cases of progressive HCV infection will be identified. The effect of HIV infection, drug use, viral heterogeneity, and genetic factors on HCV natural history will be evaluated. Prospective and nested case control analysis will be used to compare the occurrence of putative cofactors among the 50 cases and controls, matched for confounders such as the duration of drug use. After 4 years of rigorous follow-up and reassessment with liver biopsy, the relationship of hepatic histology, liver enzymes, HCV viral load and the clinical expression of disease also will be evaluated. The investigators have experience with all research methods, including assessment of HCV viral load, genotype and quasispecies distribution; HLA haplotype and gene marker characterization; liver biopsy procurement and evaluation; and analytic techniques. Success at minimal expense is likely because the study will utilize a large HCV-infected cohort, an established research setting, eight years of existing data, experienced lab personnel, and superb collaborators.